Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project

Michael L Alosco, Megan L Mariani, Charles H Adler, Laura J Balcer, Charles Bernick, Rhoda Au, Sarah J Banks, William B Barr, Sylvain Bouix, Robert C Cantu, Michael J Coleman, David W Dodick, Lindsay A Farrer, Yonas E Geda, Douglas I Katz, Inga K Koerte, Neil W Kowall, Alexander P Lin, Daniel S Marcus, Kenneth L Marek, Michael D McClean, Ann C McKee, Jesse Mez, Joseph N Palmisano, Elaine R Peskind, Yorghos Tripodis, Robert W Turner 2nd, Jennifer V Wethe, Jeffrey L Cummings, Eric M Reiman, Martha E Shenton, Robert A Stern, DIAGNOSE CTE Research Project Investigators, Charles H Adler, Michael L Alosco, Rhoda Au, Laura Balcer, Sarah Banks, William Barr, Charles Bernick, Sylvain Bouix, Robert C Cantu, Kewei Chen, Michael J Coleman, Jeffrey L Cummings, David W Dodick, Lindsay Farrer, Jennifer Fitzsimmons, Yonas Geda, Judith Goldberg, Robert Helm, Keith A Johnson, Douglas I Katz, Ivan Kirov, Inga K Koerte, Neil Kowall, Alexander P Lin, Yvonne Lui, Daniel S Marcus, Kenneth L Marek, Megan Mariani, Charles Marmar, Michael McClean, Ann C McKee, Jesse Mez, Jason Miller, Joseph N Palmisano, Ofer Pasternak, Elaine R Peskind, Hillary Protas, Eric Reiman, Aaron Ritter, Martha E Shenton, Robert A Stern, Yi Su, Yorghos Tripodis, Robert W Turner, Jason Weller, Jennifer V Wethe, Michael L Alosco, Megan L Mariani, Charles H Adler, Laura J Balcer, Charles Bernick, Rhoda Au, Sarah J Banks, William B Barr, Sylvain Bouix, Robert C Cantu, Michael J Coleman, David W Dodick, Lindsay A Farrer, Yonas E Geda, Douglas I Katz, Inga K Koerte, Neil W Kowall, Alexander P Lin, Daniel S Marcus, Kenneth L Marek, Michael D McClean, Ann C McKee, Jesse Mez, Joseph N Palmisano, Elaine R Peskind, Yorghos Tripodis, Robert W Turner 2nd, Jennifer V Wethe, Jeffrey L Cummings, Eric M Reiman, Martha E Shenton, Robert A Stern, DIAGNOSE CTE Research Project Investigators, Charles H Adler, Michael L Alosco, Rhoda Au, Laura Balcer, Sarah Banks, William Barr, Charles Bernick, Sylvain Bouix, Robert C Cantu, Kewei Chen, Michael J Coleman, Jeffrey L Cummings, David W Dodick, Lindsay Farrer, Jennifer Fitzsimmons, Yonas Geda, Judith Goldberg, Robert Helm, Keith A Johnson, Douglas I Katz, Ivan Kirov, Inga K Koerte, Neil Kowall, Alexander P Lin, Yvonne Lui, Daniel S Marcus, Kenneth L Marek, Megan Mariani, Charles Marmar, Michael McClean, Ann C McKee, Jesse Mez, Jason Miller, Joseph N Palmisano, Ofer Pasternak, Elaine R Peskind, Hillary Protas, Eric Reiman, Aaron Ritter, Martha E Shenton, Robert A Stern, Yi Su, Yorghos Tripodis, Robert W Turner, Jason Weller, Jennifer V Wethe

Abstract

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project.

Methods: The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined.

Results: Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021.

Conclusions: Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE.

Trial registration: NCT02798185.

Keywords: Biomarkers; Chronic traumatic encephalopathy; Cognitive function; College football; Concussion; Football; Head trauma; MRI; MRS; National Football League; Neurodegenerative disease; Neuroimaging; Positron emission tomography; Remote assessment; Repetitive head impacts; Subconcussion; Tau; Traumatic brain injury; Traumatic encephalopathy syndrome.

Conflict of interest statement

MLA: None to report.

MLM: None to report.

CHA: None to report.

LJB is Editor-in-Chief of the Journal of Neuro-Ophthalmology, and is a paid consultant to Biogen (Cambridge, MA, USA).

CB receives research support from the Ultimate Fighting Championship, Top Rank promotions, Haymon Boxing, Las Vegas Raiders, and Professional Bull Riders. He is a paid consultant for Aurora Concussion Therapy Systems, Inc. (St. Paul, MN).

RA is a paid consultant to Biogen (Cambridge, MA, USA) and serves on the Scientific Advisory Board of Signant Health (Blue Bell, PA).

SJB: None to report.

WBB provides expert witness testimony in legal cases involving concussion and CTE.

SB: None to report.

RCC is a Senior Advisor to the NFL Head Neck & Spine Committee; Vice President, National Operating Committee on Standards for Athletic Equipment; and Chair, Scientific Advisory Committee, Co-Founder, and Medical Director, Concussion Legacy Foundation. He is a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation, and he receives royalties for published books from Houghton Mifflin Harcourt.

MJC: None to report.

DWD reports the following competing interests: Consulting: AEON, Amgen, Clexio, Cerecin, Cooltech, Ctrl M, Allergan, Alder, Biohaven, GSK, Linpharma, Lundbeck, Promius, Eli Lilly, eNeura, Novartis, Impel, Satsuma, Theranica, WL Gore, Nocira, XoC, Zosano, Upjohn (Division of Pfizer), Pieris, Praxis, Revance, Equinox. Honoraria: Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, MJH Lifesciences, Miller Medical Communications, Southern Headache Society (MAHEC), WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Research Support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI). Stock Options/Shareholder/Patents/Board of Directors: Ctrl M (options), Aural analytics (options), ExSano (options), Palion (options), Healint (Options), Theranica (Options), Second Opinion/Mobile Health (Options), Epien (Options/Board), Nocira (options), Matterhorn (Shares/Board), Ontologics (Shares/Board), King-Devick Technologies (Options/Board), Precon Health (Options/Board). Patent 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis.

LAF: None to report.

YEG has received research funding from Roche Inc and has been a paid consultant for Lundbeck.

DIK receives royalties from Springer/Demos Publishing for a text book on brain injury, serves as expert witness in legal cases involving brain injury and concussion, receives a stipend from Encompass Health as program medical director for brain injury and chair of the annual Neurorehabilitation conference; and has received honoraria for a keynote address for the HealthSouth annual Medical Directors meeting and some grand rounds lectures involving TBI.

IKK: None to report.

NWK: None to report.

APL is a paid consultant to Agios Pharmaceuticals (Cambridge, MA, USA), Biomarin Pharmaceuticals (Novato, CA, USA), and Moncton MRI (Moncton, Canada). He is the co-founder of BrainSpec, Inc.

DSM has an equity interest in Radiologics, Inc., White Rabbit, Inc., and Sora Neuroscience, LLC.

KLM is a consultant for the Michael J Fox Foundation, GE Healthcare, Roche, UCB, Lysosomal Therapeutic, Inc, Denali, Takeda, Samumed, Cerapsir, HANDL, Biohaven, Neuron23, Aprinoia, Hemacure, Genentech, and Invicro,

MDM: None to report.

ACM: None to report.

JM: None to report.

JNP: None to report.

EP: None to report.

YT: None to report.

RWT: None to report.

JVW: None to report.

JLC has provided consultation to Acadia, Alkahest, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Jazz, Karuna, Merck, Novo Nordisk, Otsuka, ReMYND, Resverlogix, Roche, Samumed, Samus, Signant Health, Sunovion, Suven, United Neuroscience, and Unlearn AI pharmaceutical and assessment companies. He owns the copyright of the Neuropsychiatric Inventory.

EMR is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics, and Vaxxinity, and a co-founder of ALZPath.

MES: None to report.

RAS is a paid consultant to Biogen (Cambridge, MA, USA). He is a member of the Board of Directors of King-Devick Technologies, Inc. (Chicago, IL, USA), and he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL, USA). He is a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation.

© 2021. The Author(s).

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Source: PubMed

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